Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate in Infertile Women With Thin Endometrium

Not Applicable

Completed

Conditions: Anovulation

Interventions: Drug: clomiphene citrate
Drug: Sildenafil vaginal gel

Registration Number: NCT02710981

Lead Sponsor: Assiut University

Brief Summary: This is a prospective self controlled clinical trial. Women with clomiphene Citrate failure, and thin endometrium were recruited (N = 42). In their 6th (Clomiphene citrate only) cycle, women continued on Clomiphene citrate 100 mg/ day for 5 days, and had sonographic measurement of their endometrial thickness , and Doppler evaluation of their uterine arteries on the day of HCG administration. In 7th cycle, women (N = 36) were given usual dose of Clomiphene citrate supplemented with sildenafil vagina gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 till the day of HCG injection. Endometrial thickness and uterine artery Doppler were measured on the day of HCG administration.

Detailed Description: Study design:

This is a prospective self-controlled clinical trial.

Study subjects:

Investigators counseled and recruited 42 infertile women who had been diagnosed with anovulatory infertility, with normal baseline FSH, LH, and free testosterone levels, patent tubes on hysterosalpingography, and normal male semen analysis.

By the time they were enrolled in the study, all women had already completed 5 ovulatory cycles of Clomiphene citrate induction (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) but without conception (clomiphene citrate failure) with thin endometrium (\<8mm) in at least 3 cycles. Ovulation was documented sonographically, and with day-21 serum progesterone exceeding 5 ng/ ml in all cases.

Exclusion criteria:

Women with major medical problems, male factor infertility, endocrine abnormalities such as hyperprolactinemia or abnormal thyroid functions, prior ovarian or adnexal surgery, or organic pelvic pathology were not included in the study.

Intervention:

Sixth cycle (Clomiphene citrate only):

Enrolled cases were asked to continue with Clomiphene citrate induction ( at the same dose) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG administration ( when follicular diameter reached 18 mm). Endometrial thickness and Uterine artery Doppler assessment were done in the late proliferative phase ( Day of HCG injection).

Seventh cycle ( Sildenafil vaginal gel and Clomiphene cycle):

Those who didn't conceive on the sixth cycle (41 women) were asked to have an extra (7th) cycle in which they were prescribed the usual dose of Clomiphene citrate in addition to sildenafil vaginal gel. The sildenafil vaginal gel consists of sildenafil acetate as a medicament loaded on an in situ gelling system based on two polymers: Pluronic p-127, and Hydroxy Ethyl Cellulose. The dose was 5 g gel containing 50 mg sildenafil, applied vaginally twice daily from cycle day 8 to Day of HCG injection. The gel was prepared in collaboration with the department of pharmaceutics, faculty of Pharmacy, Assiut University. Sixty grams of gel were prepared in tubes and every patient was given 10 applicators like that used for administration of vaginal antimycotic creams to use them for applying the gel.

Evaluation of the study end points:

On day of HCG injection (main follicular diameter of 18 mm) in the 6th, and 7th cycles, women came for follow up and had transvaginal sonographic assessment of their endometrial thickness. Investigators have measured the maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus. In addition, Transvaginal Doppler examination was also done on the same visit to evaluate the pulsatility indices of both uterine arteries. When the leading follicle reached 18 mm in diameter, 5000 IU of HCG was prescribed for IM injection.

Although pregnancy rate was not a primary outcome measure in the study, investigators detected pregnancy in 3 cases in the cohort of 36 cases of infertile women with clomiphene failure in which sildenafil gel was added as an adjuvant. Pregnancy was diagnosed with a B-HCG value above 100 mIU/ml, and confirmed later with ultrasound.

Statistics:

Data were analyzed using SPSS program ver. 17 using Student-t-test and Fisher's exact test for comparing data in the 6th and 7th cycles, as appropriate.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 42

Inclusion Criteria

Women with clomiphene citrate failure (defined as at least prior 5 ovulatory cycles with clomiphene citrate, with no conception),
persistently thin endometrium (less than 8 mm in at least 3 cycles).
normal baseline FSH, LH, and free testosterone levels, patent tubes on hysterosalpingography, and normal male semen analysis

Exclusion Criteria

Women with major medical problems,
male factor infertility,
endocrine abnormalities such as hyperprolactinemia or abnormal thyroid functions,
prior ovarian or adnexal surgery, or organic pelvic pathology

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Sildenafil vaginal gel and Clomiphene	Sildenafil vaginal gel	Women who did not conceive on the Clomiphene citrate only cycle (41 women) were given Clomiphene citrate 100 mg/ day starting from day of the cycle for 5 days, with the addition to sildenafil vaginal gel 5 gm twice daily starting from day 8 of the cycle until day of HCG injection.
Clomiphene citrate only	clomiphene citrate	women with prior 5 ovulatory cycles of Clomiphene citrate induction, but without conception (clomiphene citrate failure), with thin endometrium (\<8mm) in at least 3 cycles.
Sildenafil vaginal gel and Clomiphene	clomiphene citrate	Women who did not conceive on the Clomiphene citrate only cycle (41 women) were given Clomiphene citrate 100 mg/ day starting from day of the cycle for 5 days, with the addition to sildenafil vaginal gel 5 gm twice daily starting from day 8 of the cycle until day of HCG injection.

Primary Outcome Measures

Name	Time	Method
Endometrial Thickness	Day of HCG administration	Transvaginal sonographic measurement of maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus

Secondary Outcome Measures

Name	Time	Method
Uterine Blood Flow	Day of HCG administration	Doppler ultrasound is used to measure the pulsatility index in both uterine arteries. Pulsatility index is a measure of the arterial resistance to blood flow. The higher the value of the pulsatility index, the more resistant the uterine arteries are, and hence the worst the outcome.
Clinical Pregnancy Rate	At the end of a 28-day menstrual cycle.	Identifying pregnancy through positive urinary HCG test plus sonographic detection of cardiac pulsations